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The nuclear γ-H2AX apoptotic ring: implications for cancers and autoimmune diseases

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Abstract

Apoptosis is a fundamental process for metazoan development. It is also relevant to the pathophysiology of immune diseases and cancers and to the outcome of cancer chemotherapies, as well as being a target for cancer therapies. Apoptosis involves intrinsic pathways typically initiated by DNA damaging agents and engaging mitochondria, and extrinsic pathways typically initiated by “death receptors” and their ligands TRAIL and TNF at the cell surface. Recently, we discovered the apoptotic ring, which microscopically looks like a nuclear annular staining early in apoptosis. This ring is, in three-dimensional space, a thick intranuclear shell consisting of epigenetic modifications including histone H2AX and DNA damage response (DDR) proteins. It excludes the DNA repair factors usually associated with γ-H2AX in the DDR nuclear foci. Here, we summarize our knowledge of the apoptotic ring, and discuss its biological and pathophysiological relevance, as well as its value as a potential pharmacodynamic biomarker for anticancer therapies.

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Acknowledgments

We wish to thank our close laboratory colleagues for their commitment to γ-H2AX basic research: Dr. William Bonner, Dr. Christophe Redon, Dr. James H. Doroshow, and Dr. Kurt W. Kohn. We also wish to thank our NCI colleagues from the DCTD, PADIS, for the development of γ-H2AX pharmacodynamics biomarker assays: Dr. James H. Doroshow, Dr. Joseph E. Tomaszewski, Dr. Raph E. Parchment, and Dr. Robert Kinders. Our studies are supported by the NCI Intramural Program, Center for Cancer Research, NIH.

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Correspondence to Yves Pommier.

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Solier, S., Pommier, Y. The nuclear γ-H2AX apoptotic ring: implications for cancers and autoimmune diseases. Cell. Mol. Life Sci. 71, 2289–2297 (2014). https://doi.org/10.1007/s00018-013-1555-2

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